Publications by authors named "Victor S Tarabykin"

6 Publications

  • Page 1 of 1

Interleukin-10 restores glutamate receptor-mediated Ca-signaling in brain circuits under loss of transcription factor.

Int J Neurosci 2020 Aug 6:1-12. Epub 2020 Aug 6.

Laboratory of Intracellular Signaling, Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences," Russia.

Objective: This study aimed to investigate the connection between the mutation of the transcription factor and impaired Ca-signaling, which reflects changes in neurotransmission in the cerebral cortex .

Methods: We used mixed neuroglial cortical cell cultures derived from mutant mice. The cells were loaded with a fluorescent ratiometric calcium-sensitive probe Fura-2 AM and epileptiform activity was modeled by excluding magnesium ions from the external media or adding a GABA(A) receptor antagonist, bicuculline. Intracellular calcium dynamics were recorded using fluorescence microscopy. To identify the level of gene expression, the Real-Time PCR method was used.

Results: It was found that cortical neurons isolated from homozygous () mice with the mutation demonstrate suppressed Ca signals in models of epileptiform activity . Wild-type cortical neurons are characterized by synchronous high-frequency and high-amplitude Ca oscillations occurring in all neurons of the network in response to Mg-free medium and bicuculline. But cortical neurons only single Ca pulses or attenuated Ca oscillations are recorded and only in single neurons, while most of the cell network does not respond to these stimuli. This signal deficiency of neurons correlates with a suppressed expression level of the genes encoding the subunits of NMDA, AMPA, and KA receptors; protein kinases PKA, JNK, CaMKII; and also the transcription factor Hif1α. These negative effects were partially abolished when neurons are grown in media with anti-inflammatory cytokine IL-10. IL-10 increases the expression of the above-mentioned genes but not to the level of expression in wild-type. At the same time, the amplitudes of Ca signals increase in response to the selective agonists of NMDA, AMPA and KA receptors, and the proportion of neurons responding with Ca oscillations to a Mg-free medium and bicuculline increases.

Conclusion: IL-10 restores neurotransmission in neuronal networks with the mutation by regulating the expression of genes encoding signaling proteins.
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http://dx.doi.org/10.1080/00207454.2020.1803305DOI Listing
August 2020

Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury.

Cell Rep 2020 06;31(13):107834

Burke Neurological Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 1600 York Avenue, New York, NY 10065, USA; Department of Chemistry and Life Science, United States Military Academy, West Point, NY 10996, USA. Electronic address:

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. In mouse models of either contusive spinal cord injury or transient ischemic stroke, the conditional knockout of Zeb2 in astrocytes attenuates astrogliosis, generates larger lesions, and delays the recovery of motor function. These findings reveal ZEB2 as an important regulator of the astrocytic response to injury and suggest that astrogliosis is an EMT-like process, which provides a conceptual connection for the molecular and cellular similarities between astrogliosis and wound-healing responses in non-neural tissue.
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http://dx.doi.org/10.1016/j.celrep.2020.107834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416489PMC
June 2020

Delineation of Clinical Manifestations of the Inherited Xq24 Microdeletion Segregating with sXCI in Mothers: Two Novel Cases with Distinct Phenotypes Ranging from UBE2A Deficiency Syndrome to Recurrent Pregnancy Loss.

Cytogenet Genome Res 2020 30;160(5):245-254. Epub 2020 May 30.

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.
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http://dx.doi.org/10.1159/000508050DOI Listing
September 2020

Intracellular Neuroprotective Mechanisms in Neuron-Glial Networks Mediated by Glial Cell Line-Derived Neurotrophic Factor.

Oxid Med Cell Longev 2019 18;2019:1036907. Epub 2019 Nov 18.

Lobachevsky State University of Nizhni Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod 603950, Russia.

Glial cell line-derived neurotrophic factor (GDNF) has a pronounced neuroprotective effect in various nervous system pathologies, including ischaemic brain damage and neurodegenerative diseases. In this work, we studied the effect of GDNF on the ultrastructure and functional activity of neuron-glial networks during acute hypoxic exposure, a key damaging factor in numerous brain pathologies. We analysed the molecular mechanisms most likely involved in the positive effects of GDNF. Hypoxia modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). GDNF (1 ng/ml) was added to the culture medium 20 min before oxygen deprivation. Acute hypoxia-induced irreversible changes in the ultrastructure of neurons and astrocytes led to the loss of functional Сa activity and neural network disruption. Destructive changes in the mitochondrial apparatus and its functional activity characterized by an increase in the basal oxygen consumption rate and respiratory chain complex II activity during decreased stimulated respiration intensity were observed 24 hours after hypoxic injury. At a concentration of 1 ng/ml, GDNF maintained the functional metabolic network activity in primary hippocampal cultures and preserved the structure of the synaptic apparatus and number of mature chemical synapses, confirming its neuroprotective effect. GDNF maintained the normal structure of mitochondria in neuronal outgrowth but not in the soma. Analysis of the possible GDNF mechanism revealed that RET kinase, a component of the receptor complex, and the PI3K/Akt pathway are crucial for the neuroprotective effect of GDNF. The current study also revealed the role of GDNF in the regulation of HIF-1 transcription factor expression under hypoxic conditions.
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http://dx.doi.org/10.1155/2019/1036907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885812PMC
April 2020

Mutation in the Sip1 transcription factor leads to a disturbance of the preconditioning of AMPA receptors by episodes of hypoxia in neurons of the cerebral cortex due to changes in their activity and subunit composition. The protective effects of interleukin-10.

Arch Biochem Biophys 2018 09 27;654:126-135. Epub 2018 Jul 27.

Institute of Cell Biophysics, Russian Academy of Sciences, Russia. Electronic address:

The Sip1 mutation plays the main role in pathogenesis of the Mowat-Wilson syndrome, which is characterized by the pronounced epileptic symptoms. Cortical neurons of homozygous mice with Sip1 mutation are resistant to AMPA receptor activators. Disturbances of the excitatory signaling components are also observed on such a phenomenon of neuroplasticity as hypoxic preconditioning. In this work, the mechanisms of loss of the AMPA receptor's ability to precondition by episodes of short-term hypoxia were investigated on cortical neurons derived from the Sip1 homozygous mice. The preconditioning effect was estimated by the level of suppression of the AMPA receptors activity with hypoxia episodes. Using fluorescence microscopy, we have shown that cortical neurons from the Sip1 mice are characterized by the absence of hypoxic preconditioning effect, whereas the amplitude of Ca-responses to the application of the AMPA receptor agonist, 5-Fluorowillardiine, in neurons from the Sip1 mice brainstem is suppressed by brief episodes of hypoxia. The mechanism responsible for this process is hypoxia-induced desensitization of the AMPA receptors, which is absent in the cortex neurons possessing the Sip1 mutation. However, the appearance of preconditioning in these neurons can be induced by phosphoinositide-3-kinase activation with a selective activator or an anti-inflammatory cytokine interleukin-10.
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http://dx.doi.org/10.1016/j.abb.2018.07.019DOI Listing
September 2018

Sip-1 mutations cause disturbances in the activity of NMDA- and AMPA-, but not kainate receptors of neurons in the cerebral cortex.

Neurosci Lett 2017 05 25;650:180-186. Epub 2017 Apr 25.

Institute of Biology and Biomedicine, Lobachevsky State University of Nizhniy Novgorod, Russia; Institute of Cell Biophysics, Russian Academy of Sciences, Russia. Electronic address:

Smad-interacting protein-1 (Sip1) [Zinc finger homeobox (Zfhx1b), Zeb2] is a transcription factor implicated in the genesis of Mowat-Wilson syndrome (MWS) in humans. MWS is a rare genetic autosomal dominant disease caused by a mutation in the Sip1 gene (aka Zeb2 or Zfhx1b) mapped to 2q22.3 locus. MWS affects 1 in every 50-100 newborns worldwide. It is characterized by mental retardation, small stature, typical facial abnormalities as well as disturbances in the development of the cardio-vascular and renal systems as well as some other organs. Sip1 mutations cause abnormal neurogenesis in the brain during development as well as susceptibility to epileptic seizures. In the current study we investigated the role of the Sip1 gene in the activity of NMDA-, AMPA- and KA- receptors. We showed that a particular Sip1 mutation in the mouse causes changes in the activity of both NMDA- and AMPA- receptors in the neocortical neurons in vitro. We demonstrate that neocortical neurons that have only one copy of Sip1 (heterozygous, Sip1), are more sensitive to both NMDA- and AMPA- receptors agonists as compared to wild type neurons (Sip1). This is reflected in higher amplitudes of agonist induced Ca signals as well as a lower half maximal effective concentration (ЕC50). In contrast, neurons from homozygous Sip1 mice (Sip1), demonstrate higher resistance to these respective receptor agonists. This is reflected in lower amplitudes of Ca-responses and so a higher concentration of receptor activators is required for activation.
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http://dx.doi.org/10.1016/j.neulet.2017.04.048DOI Listing
May 2017